All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Obstructive sleep apnea (OSA) is a prevalent disorder characterized by recurrent apneas during sleep, despite persisting respiratory effort. The cessation of respiration is due to obstruction of the upper airway, and induces hypoxia and hypercapnia, accompanied by cardiac arrhythmias and elevations of systemic and pulmonary arterial blood pressure (Mansfield et al., “Obstructive sleep apnoea, congestive heart failure and cardiovascular disease,” Heart Lung Circ, vol. 14 Suppl 2, pp. S2-7, 2005; Peters, “Obstructive sleep apnea and cardiovascular disease,” Chest, vol. 127, pp. 1-3, 2005; O'Donnell et al., “Airway obstruction during sleep increases blood pressure without arousal,” J Appl Physiol, vol. 80, pp. 773-81, 1996; O'Donnell et al., “The effect of upper airway obstruction and arousal on peripheral arterial tonometry in obstructive sleep apnea,” Am J Respir Crit Care Med, vol. 166, pp. 965-71, 2002). OSA is a strong risk factor for stroke, hypertension, atherosclerosis, cardiovascular disease, and increased postoperative morbidity after general anesthesia (Yaggi et al., “Obstructive sleep apnea as a risk factor for stroke and death,” N Engl J Med, vol. 353, pp. 2034-41, 2005; He et al., “Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients,” Chest, vol. 94, pp. 9-14, 1988). The frequent partial arousals throughout the night result in sleep deprivation and daytime tiredness and malaise.
Sleep-disordered breathing affects up to 9% of working-aged women and 24% of men (Peters, “Obstructive sleep apnea and cardiovascular disease,” Chest, vol. 127, pp. 1-3, 2005). Total collapse of the airway with complete obstruction lasting 10 second or more and with a decrease in arterial oxyhemoglobin saturation of 4% or more is classified as OSA. Partial airway obstruction sufficient to cause a decrease in oxyhemoglobin saturation of 4% or more is designated as obstructive hypopnea. The severity of OSA usually is quantified by an apnea-hypoxia index (AHI), the number of apneic and hypoxic episodes per hour of sleep. The nearly universal use of the AHI recorded during polysomnography to characterize OSA has been criticized as being at best a surrogate for the cardiovascular effect of the disorder. For example, an AHI of 15 consisting exclusively of hypopneas and minor oxyhemoglobin desaturation (about 4-5% from baseline) would be of much less cardiovascular significance than the same AHI accompanied by severe hypoxia and hypercapnia. Thus repeated, transient oxyhemoglobin desaturation to 93% or less markedly increases mean arterial blood pressure (O'Donnell et al., “Airway obstruction during sleep increases blood pressure without arousal,” J Appl Physiol, vol. 80, pp. 773-81, 1996). While criteria for clinical staging of OSA appear not to be well standardized, an AHI of about 5 to about 27 is generally considered mild-to-moderate OSA. This reflects the assumption that “normal” individuals may experience up to 5 episodes of hypopnea or apnea per hour with oxyhemoglobin desaturation of 4% or greater, and also the consensus that more than 5 such episodes per hour are associated with at least some increased risk of cardiovascular disease (Meoli et al., “Hypopnea in sleep-disordered breathing in adults,” Sleep, vol. 24, pp. 469-70, 2001). Persons with severe OSA may experience 30 or more episodes per hour. Persons with an AHI of 20 or greater have markedly increased mortality relative to the general population (He et al., “Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients,” Chest, vol. 94, pp. 9-14, 1988). Moderate-to-severe OSA is estimated to occur in at least 1-4% of working-aged adults in the generation population, with about a 2:1 preference for males, but a significant number of affected persons remain undiagnosed, so the prevalence may be considerably greater (Stierer et al., “Demographics and diagnosis of obstructive sleep apnea,” Anesthesiol Clin North America, vol. 23, pp. 405-20, v, 2005).
A cardinal feature of OSA is the tendency for the soft tissues of the upper airway, specifically those of the velo- and oropharynx, to collapse during sleep, and thus occlude the airway. In healthy persons during sleep, the critical pressure for airway collapse (Pcrit) ranges from about 0 to about −14 cm H2O so that a small partial vacuum within the airway is required in order to induce collapse (King et al., “A model of obstructive sleep apnea in normal humans. Role of the upper airway,” Am J Respir Crit Care Med, vol. 161, pp. 1979-84, 2000). However, “healthy” persons in which Pcrit during sleep is close to 0 cm H2O tend to snore. For persons with OSA, as in healthy persons, the background tone in the muscles of the upper airway, and also phasic activity in the hypoglossal nerve associated with airway protective reflexes, maintain a negative Pcrit during wakefulness. However, during sleep, and especially during REM sleep, the reduction in the activity in the hypoglossal nerve results in a reduction in the tone and stiffness in the muscles of the upper airway, causing Pcrit to rise to or above atmospheric pressure, rendering the upper airway vulnerable to collapse. (Smith et al., “Upper airway pressure-flow relationships in obstructive sleep apnea,” J Appl Physiol, vol. 64, pp. 789-95, 1988). The physiological and anatomical factors responsible for the elevated Pcrit in persons with OSA are complex and vary between patients, suggesting the need for treatment options that can be tailored to each patient's needs (Ryan et al., “Pathogenesis of obstructive sleep apnea,” J Appl Physiol, vol. 99, pp. 2440-50, 2005).
A reduction in the tone of the muscles of the tongue base during sleep is an important contributor to the elevated Pcrit in persons with OSA. Also, in response to the decreased tone in the tongue extensor muscles, particularly the geneoglossus muscle, the tongue tends to prolapse onto the back of the pharynx, partially obstructing the airway (Feldman et al., “Slip of the tongue,” Am J Respir Crit Care Med, vol. 170, pp. 581-2, 2004).
Continuous positive airway pressure by a nasal mask (nasal CPAP) relieves OSA by maintaining the airway at a positive pressure, slightly above Pcrit (Smith et al., “Upper airway pressure-flow relationships in obstructive sleep apnea,” J Appl Physiol, vol. 64, pp. 789-95, 1988). There remains some controversy as to whether the effect is purely a passive inflation of the airway (“pneumatic splinting”) or if the positive pressure also triggers protective airway reflexes (Goh et al., “Upper airway dilating forces during wakefulness and sleep in dogs,” J Appl Physiol, vol. 61, pp. 2148-55, 1986). CPAP is very effective and currently is the gold standard for non-surgical treatment of moderate-to-severe OSA. However, the firm-fitting nasal mask and the associated hose line are often uncomfortable and encumbering, the sensation of continuous positive airway pressure is uncomfortable and disconcerting to many users and the device is generally regarded as a necessary evil, even by well-acclimated users. It has been reported that 8-15% of OSA patients refuse further use of CPAP after the first night (Krieger, “Therapeutic use of auto-CPAP,” Sleep Med Rev, vol. 3, pp. 159-74, 1999). While CPAP technology has improved and protocols for achieving primary acceptance by patients also have been evolving in recent years, even “regular users” often employ their CPAP during only part of the night (e.g., 3.5-5 hours) and tend not to use it every night (Valenca et al., “[Compliance to positive airway pressure treatment in obstructive sleep apnea syndrome (OSAS).],” Rev Port Pneumol, vol. 11, pp. 52-3, 2005; Orth et al., “[Long-term compliance of cpap-therapy—update, predictors and interventions],” Pneumologie, vol. 60, pp. 480-4, 2006; Sin et al., “Long-term compliance rates to continuous positive airway pressure in obstructive sleep apnea: a population-based study,” Chest, vol. 121, pp. 430-5, 2002). These persons are likely to remain at somewhat elevated risk for the cardiovascular complications of OSA, even if their compliance is adequate to allow sufficient restorative sleep to markedly improve the quality of day-to-day life. Clearly there is a need for effective alternatives to CPAP that will find better initial acceptance and long-term compliance. Such alternatives could be of considerable significance to public health if they also achieve greater initial acceptance and compliance by persons with moderate OSA, since this may prevent or delay progression to more severe stages. There is evidence that the chronic intermittent hypoxias of OSA lead to a conversion of the pharyngeal muscle fibers, which further increase collapsibility. Animal studies have demonstrated that after 10 hours of intermittent hypoxia, the geneoglossus muscle undergoes a conversion to myosin chain type 2A to 2B, which are much more fatigable (Pae et al., “Geniohyoid muscle properties and myosin heavy chain composition are altered after short-term intermittent hypoxic exposure,” J Appl Physiol, vol. 98, pp. 889-94, 2005). Thus, In addition to the effects of sleep depravation on the respirator drive and the activity of the pharyngeal muscles, and compromise of protective airway reflexes by the reduced mechanical sensitivity of the pharyngeal mucosa, the intermittent hypoxia also promotes increased collapsibility of the upper airway (O'Halloren et al., “Chronic intermittent asphyxia impairs rat upper airway muscle responses to acute hypoxia and asphyxia,” Chest, vol. 122, pp. 269-75, 2002, Bradford et al., “Does episodic hypoxia affect upper airway dilator muscle function? Implications for the pathophysiology of obstructive sleep apnoea,” Respir Physiol Neurobiol, vol. 147, pp. 223-34, 2005).
Electrical stimulation of the hypoglossal nerve or of its branches innervating the geneoglossus muscle (the tongue's primary protruder muscle) has been shown to increase airflow in persons with OSA (Eiesel et al., “Direct hypoglossal nerve stimulation in obstructive sleep apnea,” Arch Otolaryngol Head Neck Surg, vol. 123, pp. 57-61, 1997; Eiesel et al., “Tongue neuromuscular and direct hypoglossal nerve stimulation for obstructive sleep apnea,” Otolaryngol Clin North Am, vol. 36, pp. 501-10, 2003; Schwartz et al., “Electrical stimulation of the lingual musculature in obstructive sleep apnea,” J Appl Physiol., vol. 81, pp. 643-652, 1996; Schwartz et al., “Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea,” Arch. Otolaryngol Head Neck Surg, vol. 127, pp. 1216-1223, 2001; Oliven et al., “Sublingual electrical stimulation of the tongue during wakefulness and sleep,” Respir Physiol, vol. 127, pp. 217-26, 2001; Oliven et al., “Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea,” J Appl Physiol, vol. 95, pp. 2023-9, 2003). Oliven et al. (2001, 2003) applied the sublingual stimulation through electrodes with large surface areas (conductive rubber) using biphasic, voltage-controlled pulses at 50 Hz and 200 μs/ph. The stimulation produced extension of the tongue and increased inspirational air flow rate in patients with OSA but did not produce arouser from sleep, as determined by the electroencephalogram. During sublingual electrical stimulation, inspired airflow increased from 58±16 ml/sec to 270±35 ml/sec in patients with severe OSA. This range of flow rates was still slightly below that of normal subjects during sleep (319±24 ml/sec). Unfortunately oxyhemoglobin desaturation was not measured in these subjects. However, in subjects without OSA, autonomic cardiovascular responses and arousal from sleep were triggered only when inspired air flow dropped below about 200 ml/sec, while mild airway obstruction had no effect (O'Donnell et al., “The effect of upper airway obstruction and arousal on peripheral arterial tonometry in obstructive sleep apnea,” Am J Respir Crit Care Med, vol. 166, pp. 965-71, 2002).
Schwartz et al. (1996) determined that electrical stimulation of tongue protruder muscles increased airflow in OSA patients, while stimulation of tongue retractors decreased air flow. However Oliven et al. (2001) found that electrical stimulation of the posterior and also of the anterior surface of the tongue was more effective in increasing airflow than was electrical stimulation of the anterior surface alone, which nonetheless produced preferential activation of the of the geneoglossus muscle, and thus the greatest protrusion of the tongue. This suggests that the increased stiffness of the tongue induced by the electrical stimulation of antagonistic muscles (retractors and protruders) decreased Pcrit (Oliven et al., “Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea,” J Appl Physiol, vol. 95, pp. 2023-9, 2003) and this action was at least as important as the tongue protrusion per se in preventing collapse of the upper airway during sleep. Indeed, there have been conflicting reports as to whether passive extension of the flaccid tongue by retaining devices is effective in treating OSA (Rose et al., “Orthodontic proceedures in the treatment of obstructive sleep apnea in children,” J Orofac Orthop, vol. 67, pp. 58-67, 2006; Higurashi et al., “Effectiveness of a tongue-retaining device,” Psychiatry Clin Neurosci, vol. 56, pp. 331-2, 2002). In patients with OSA, the sublingual stimulation caused a decrease in Pcrit during sleep whether the obstruction was in the velopharynx or in the oropharaynx, just as did electrical stimulation of the trunk of the hypoglossal nerve itself. This is an important observation since either or both regions may collapse during OSA. It is notable that these studies were conduced with nasal breathing, with the inspired air passing behind, rather than over, the tongue.
Oliven et al. (2003) found that electrical stimulation of the geneoglossus and associated muscles decreased Pcrit by an average of 3.18 cm H2O in persons with OSA. By way of comparison, Smith et al. (1988) measured Pcrits of 1 to 10 cm H2O in 6 persons with OSA, but in 5 of the 6 patients, Pcrit was between 1 and 2.7 cm H2O. This, and the finding that airflow rates in these OSA patients increased to 270±35 ml/sec suggests that sublingual stimulation, and/or an approach that induces reflex activation of tongue protruder muscles with some co-activation of tongue retractors muscles, should prevent airway collapse in a significant fraction of OSA patients, provided that their Pcrit is not extremely high. However, sublingual electrical stimulation was in most cases not able to open the airway during complete apnea (Oliven et al., “Sublingual electrical stimulation of the tongue during wakefulness and sleep,” Respir Physiol, vol. 127, pp. 217-26, 2001). This important finding illustrates the potential value of a “proactive” approach of the type proposed herein by the inventor, in which the electrical stimulation is applied when the tongue just begins to retract and loose muscle tone, and to initiate activation of tongue musculature before the airway actually becomes occluded.